The International Serious Adverse Event Consortium (iSAEC) is a nonprofit, bio-medical research organization founded in 2007. It is comprised of leading pharmaceutical companies, the Wellcome Trust, and academic institutions; with scientific and strategic input from the U.S. Food and Drug Administration (FDA) and other international regulatory bodies. The mission of the iSAEC is to identify DNA-variants useful in understanding the risk of drug-related serious adverse events (SAEs).

Patients respond differently to medicines and all medicines can have side effects in certain individuals. The iSAEC’s work is based on the hypothesis these differences have (in part) a genetic basis, and its research studies examine the impact of genetic variation on how individuals respond to a large variety of medicines. The iSAEC’s initial studies have successfully identified genetic variants associated with drug-related liver toxicity (DILI) and Serious Skin Rashes (SSR). The majority of the iSAEC’s genetic findings have been specific to a given drug versus across multiple drugs. However, a number of cross drug genetic alleles are starting to emerge that may provide important insights into the underlying biology/mechanism of drug induced SAEs (e.g. HLA*5701 or UGT1A1*28). Our findings clearly demonstrate an important role for the MHC genomic region (Chromosome 6), in the pathology of immunologically mediated SAEs such as DILI and SSR. They also emphasize the importance of immune regulation genes, in addition to a number of well characterized drug metabolism (ADME) genes.

In the iSAEC’s second phase (2010-2015) we are developing novel, international clinical networks to deepen our understanding of the genetics of the following SAEs (across a diverse range of ethnic populations):

• Hepatotoxicity (DILI)
• Serious Skin Rash (DISI)
• Acute Hypersensitivity Syndrome (DRESS)
• Nephrotoxicity (DIRI)
• TdP/PQT effects (DITdP)
• Excessive Weight Gain (associated with Class 2 Anti-Psychotic Medications)
• IBD Therapy Related SAEs (4 different phenotypes)
• Jaw Osteonecrosis (ONJ)

We will continue to apply state of the art genomic methods to fulfill these aims, including whole genome genotyping and next generation sequencing to explore the role “rare” genetic variants in drug induced SAEs.

In addition to supporting original genomic research on drug-related SAEs, the iSAEC is:

• Executing "open-use research practices and standards" in all its collaborations.
• Encouraging greater research efficiency and “speed to results” by pooling talent and resources, under a collaborative private sector leadership model, solely focused on research quality and productivity.
• Releasing all of its novel genetic discoveries/associations into the public domain uninhibited by intellectual property constraints.
• Enhancing the public’s understanding of how the industry, academia and government are partnering to address drug-related adverse events.

The iSAEC assists in organizing and funding a variety of international research networks to aggregate case collection of appropriate scale and diversity (i.e. ethnicity and causal drug). We are conducting pilot initiatives that leverage electronic medical records and related databases to potentially identify individuals with relevant SAEs, in greater scale and number. These well-characterized clinical databases, from individuals who have experienced a SAE, are being compared with control cases to identify genetic variants that may be associated with the specific SAE. The identification of such genetic variants is believed to be essential to developing safer drugs, while also identifying patient populations for whom a medicine will have the greatest likelihood of providing medical benefits with the fewest risks.